Field of the Invention
The invention generally relates to the detection of symmetrical dimethylarginine (SDMA). More particularly, the invention relates to analogs that may be used to generate anti-SDMA antibodies, the anti-SDMA antibodies generated using the SDMA analogues, and uses for anti-SDMA antibodies, including diagnostic methods and devices.
Related Art
It is important to be able to measure renal function quickly and accurately. For example, the dosing of drugs must be adapted for patients with renal insufficiency. Thus, making an accurate assessment of renal function is a requirement in clinical medicine. However, the diagnosis of renal insufficiency is hindered by the lack of reliable markers of glomerular filtration rate (GFR) and/or available diagnostic tests. A widely used measurement of GFR is inulin clearance, but this test is cumbersome and expensive, which essentially reduces its utility in clinical practice. This also holds true for radioisotope clearance tests. Therefore, in clinical practice, serum creatinine is typically used to assess renal function.
A major disadvantage associated with measuring serum creatinine, however, is that there is considerable inter-individual variability associated with muscle mass, protein intake, age, and sex. Furthermore, even after a large part of a patient's renal function is lost, serum creatinine levels may remain in a normal range, meaning that serum creatinine is not useful for early detection of renal insufficiency. Moreover, while approximation of GFR by creatinine clearance can be more informative than serum creatinine, obtaining accurate 24 hour timed urine collections are labor-intensive, and may be difficult depending upon the patient population being tested, such as infants, elderly, individuals with urologic abnormalities, or animals. Accordingly, there is a need for alternative diagnostic markers and methods for testing for renal function.
Symmetrical dimethylarginine (SDMA) is the structural isomer of the endogenous nitric oxide synthetase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Both ADMA and SDMA derive from intranuclear methylation of L-arginine residuals and are released into the cytoplasm after proteolysis. SDMA is produced by protein-arginine methyltransferase 5 (PRMT 5) and PRMT 7. Proteins carrying methylarginines, such as SDMA, monomethylarginine and ADMA, play a role in RNA processing, protein shuttling and signal transduction (Bedford and Richard, Mol. Cell, 2005, April 29, 18(3):263-72). Free SDMA resulting from the degradation of such methylated proteins is mainly eliminated by renal excretion, whereas ADMA is largely metabolized.
ADMA is strongly correlated with risk factors for coronary artery disease (CAD) such as hypertension, hypercholesterolemia, hyperhomocysteinemia, insulin resistance, age, and mean arterial pressure. SDMA is correlated with parameters of renal function, such as glomerular filtration rate (GFR), inulin clearance, and creatinine clearance. SDMA, however may be more than an indicator of renal function. For example, in animals, a high-fat, high-cholesterol diet increases SDMA serum levels without affecting renal function, indicating that SDMA may also be a cardiovascular risk factor. Moreover, anti-SDMA antibodies may also be utilized as a biomarker for systemic lupus erythematosus (SLE). The D1 and D3 proteins of the Sm complex, which has been implicated to play a role in the etiology of SLE, contain C-terminal SDMA.
Accordingly, the inventors have identified a need in the art for a simple, convenient and cost effective method for identifying SDMA in biological samples to assess, for example, renal function, cardiovascular function, and SLE. Also, the inventors have identified the need to provide anti-SDMA antibodies that are specific of SDMA, i.e., that discriminate between molecules that differ only in the methylation state of the two equivalent nitrogens on the guanidino group of SDMA, such as arginine, monomethylarginine, and ADMA.